NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487.
NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487.
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NEIL 1和NEIL 2在OGG1耗尽或被TH5487抑制后被招募为OGG1的潜在备份。
DOI：
10.3390/ijms22094542
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发表时间：
2021-04-27
影响因子：
5.6
通讯作者：
Mortusewicz O
中科院分区：
文献类型：
--
作者：
Hanna BMF;Michel M;Helleday T;Mortusewicz O
由活性氧引起的DNA损伤可能导致基因突变或细胞死亡。碱基切除修复(BER)是修复DNA氧化损伤以保持基因组完整性的主要途径。在哺乳动物中，有11种DNA糖基酶被报道可以启动BER，每种酶都识别一些相关的DNA底物损伤，具有一定程度的重叠特异性。7，8-二氢-8-氧鸟嘌呤(8-oxoG)是最丰富的DNA氧化损伤之一，主要由8-oxoguanine DNA糖基酶1(OGG1)识别和切除。8-oxoG的进一步氧化会产生被Neil糖基酶识别的海因损伤。在这里，我们证明了NEIL1，以及较小程度的NEIL2，可以在药物抑制或耗尽OGG1时潜在地作为OGG1的备用BER酶。在OGG1抑制剂TH5487处理的细胞中，NEIL1的募集动力学和DNA损伤诱导后的染色质结合呈剂量依赖性地增加，而在OGG1抑制后，NEIL2在DNA损伤部位的积累延长。此外，OGG1的耗尽会导致NEIL1和NEIL2在受损染色质处的保留率增加。重要的是，氧化应激的NEIL1或NEIL2耗竭细胞在OGG1抑制时显示出过量的基因组8-oxoG损伤积聚，这表明NEIL1和NEIL2具有潜在的补偿作用。因此，我们的研究举例说明了碱基切除修复途径中可能的备份机制。
DNA damage caused by reactive oxygen species may result in genetic mutations or cell death. Base excision repair (BER) is the major pathway that repairs DNA oxidative damage in order to maintain genomic integrity. In mammals, eleven DNA glycosylases have been reported to initiate BER, where each recognizes a few related DNA substrate lesions with some degree of overlapping specificity. 7,8-dihydro-8-oxoguanine (8-oxoG), one of the most abundant DNA oxidative lesions, is recognized and excised mainly by 8-oxoguanine DNA glycosylase 1 (OGG1). Further oxidation of 8-oxoG generates hydantoin lesions, which are recognized by NEIL glycosylases. Here, we demonstrate that NEIL1, and to a lesser extent NEIL2, can potentially function as backup BER enzymes for OGG1 upon pharmacological inhibition or depletion of OGG1. NEIL1 recruitment kinetics and chromatin binding after DNA damage induction increase in cells treated with OGG1 inhibitor TH5487 in a dose-dependent manner, whereas NEIL2 accumulation at DNA damage sites is prolonged following OGG1 inhibition. Furthermore, depletion of OGG1 results in increased retention of NEIL1 and NEIL2 at damaged chromatin. Importantly, oxidatively stressed NEIL1- or NEIL2-depleted cells show excessive genomic 8-oxoG lesions accumulation upon OGG1 inhibition, suggesting a prospective compensatory role for NEIL1 and NEIL2. Our study thus exemplifies possible backup mechanisms within the base excision repair pathway.
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影响因子：
2.9
作者：
Krishnamurthy, Nirmala;Zhao, Xiaobei;David, Sheila S.
通讯作者：
David, Sheila S.
影响因子：
4.8
作者：
Katafuchi, A;Nakano, T;Ide, H
通讯作者：
Ide, H
影响因子：
4.8
作者：
Dou, H;Mitra, S;Hazra, TK
通讯作者：
Hazra, TK
DOI：
10.1073/pnas.062053799
发表时间：
2002-03-19
影响因子：
11.1
作者：
Hazra, TK;Izumi, T;Mitra, S
通讯作者：
Mitra, S
影响因子：
4.1
作者：
Michel, Maurice;Visnes, Torkild;Helleday, Thomas
通讯作者：
Helleday, Thomas